When barriers are broken, infections occur. Surgery, trauma and burns, medical instrumentation (e.g., catheterization, ventilation), chronic wounds (e.g., diabetic foot ulcers) and a variety of diseases disrupt our natural barriers of defense. In nearly all cases, these “wounds” become contaminated with microbes. Then, the terrain of wounds provides an excellent environment for microbial growth. The battle begins, and it's trench warfare. Damaged tissues (“cracks and crevices”), altered blood flow and exudate production, changes in local temperature, pH and tissue oxygenation, as well as the lack of commensal bacteria, can all contribute. Also, bleeding and vascular leakage may provide fluids and nutrients that ultimately support microbial growth. Bacterial or fungal colonization, and/or overt infection may occur. Microbial biofilms can help microbes to create their own local environments. Various surgical, trauma and medical settings all involve disruption of our natural barriers of defense and deserve special attention because the outcomes can range from rapid cure to lethal sepsis.
Natural barriers are typically referred to by their anatomical sites such as skin, pulmonary epithelium, gastrointestinal mucosa, etc. These names may imply a level of simplicity that is unwarranted. These barriers are often both passive and active. They can involve a variety of cells, secreted glycoproteins, matrix components and fluids that act in concert to provide effective defense against microbial invasion. In some sites, resident microbes contribute to the barrier action against other potential invaders. Under most circumstances, these physical and functional barriers are highly effective. However, they can be broken rather easily by mechanical or chemical insults. In addition, certain systemic diseases can weaken our natural barriers and increase the risk of breakdown, as occurs in diabetic foot ulcers or cystic fibrosis. Finally, a first infection can weaken host defenses against a second infection, as occurs in influenza followed by bacterial pneumonia or trichomonas vaginalis followed by certain sexually transmitted diseases (e.g., HIV).
Broken barriers of defense leave the host susceptible to infection by a wide variety of microbes, ranging from typically benign commensal organisms to aggressive pathogens. Commonly, we are our own source of the microbes that contaminate our wounds. The human body hosts a very large number of bacteria, predominately on skin, in mouths and within lower GI tracts. It has been estimated that there are more bacterial cells (1014) than mammalian cells (1013) within the space of one human body. Despite this close relationship with microbes, most of our tissues (including blood, subcutaneous tissue, muscle, brain) remain sterile until the disruption of the natural barriers. Other people and environmental sources of microbes are also important, especially in healthcare settings. Once a barrier is broken, microbial contamination, critical level colonization, biofilm formation and/or overt infection may occur. Polymicrobial colonization and/or infection is common in certain settings (e.g., diabetic foot ulcers, complex intra-abdominal infections), and may involve aerobes, anaerobes or both.
Prior approaches to the prevention and treatment of these infections have demonstrated substantial weaknesses. Both lack of effectiveness and tissue toxicity have been challenges. Antimicrobials often fail to get to the right tissue spaces and/or fail to remain active for sufficient time to prevent or treat infection. Complex surfaces like those of the abdominal cavity or large burns are particularly difficult to cover effectively. Finally, safe application of sufficient antimicrobial materials into certain tissue spaces (such as through laparoscopic or arthroscopic equipment) can be challenging. Antimicrobials that are readily applied by these methods tend to be solution-based materials with limited ability to bind tissues and remain active over time.
Biofilms present a particular challenge. Increasing evidence points to the resistance of bacterial biofilms to a variety of antimicrobial approaches and to their role in adverse patient outcomes. These microbial communities resist traditional antiseptics and antibiotics through several mechanisms, including, but not limited to, their own production of extracellular polymeric substances, which are often negatively charged (anionic). Penetration of these materials by traditional antimicrobials is often limited. For example, in acute wounds (e.g. surgery and trauma), devitalized tissue and foreign bodies (e.g., prosthetic implants) may support biofilm formation and thereby increase the probability of overt infection. In chronic wounds (e.g. diabetic foot ulcers), biofilms may persist and lead to delayed wound healing. Medical instruments like ventilators and catheters can be a site of biofilm formation and provide a source of infection.
Antimicrobial treatment of early infections may alter the course of the infection, resulting in more resistant and more dangerous infections. Common antimicrobial strategies focus on the use of selective antibiotics (e.g., penicillin for gram-positive organisms) in order to avoid the development of bacteria that are resistant to broad-spectrum antibiotics. Inadvertently, this important strategy can have negative outcomes on an individual patient, where targeted antibiotics result in the emergence of an aggressive, different microorganism (e.g., Pseudomonas). In this way, treated wounds can become the site for a “parade of pathogens”, where an early, dominant microbial species (e.g., Staph aureus) is replaced by a second (e.g., MRSA, methicillin-resistant Staph aureus) and, perhaps, even a third and fourth microbial species (e.g., a multi-drug resistant gram negative species).
The large numbers of adverse patient outcomes in today's advanced healthcare settings underscore the inadequacies of prior art in the prevention and treatment of these infections. Several key weaknesses include:
1. Low antimicrobial activity in tissue settings and on biofilms;
2. Inadequate distribution to the relevant tissue space;
3. Limited, if any, barrier activity;
4. Narrow breadth of antimicrobial activity enables the “parade of pathogens”;
5. Inadequate treatment fosters more antimicrobial resistance; and/or
6. Tissue toxicity.
Infections of wounds and other broken-barrier settings are common and costly. In the US alone, approximately 12 million traumatic injuries are treated in emergency departments each year. In addition, there are more than 50 million surgeries (inpatient and outpatient). The US Department of Health and Human Services indicates that there are more than 1.7 million healthcare-associated infections annually, resulting in approximately 100,000 deaths and $30 billion in healthcare costs per year. Many of these healthcare-associated infections start with broken barriers. Examples include surgical site infections (SSIs), catheter-associated urinary tract infections and ventilator-associated pneumonia. The chronic wounds associated with pressure ulcers (bed sores) and diabetic foot ulcers present their own unique challenges.
In addition to infection, several other wound-associated outcomes remain major challenges. These include blood loss, tissue adhesions/scarring, and poor wound healing. And, in some cases, known antimicrobial treatments make these problems worse. Certain antimicrobial wound treatments (including antibiotic washes) can result in excessive tissue responses (e.g., tissue adhesions or scarring). Certain antiseptic/antimicrobial materials may alter wound healing, resulting in insufficient tissue responses (e.g., poor wound healing, poor wound strength).
Effective hemostasis in wounds also remains a substantial problem. Hemostatic materials have been described and are utilized in a variety of settings, including in trauma and in surgery. While effective in some situations, these materials do not provide ideal solutions to the challenges. First, there are times when the hemostasis is insufficient and too much bleeding occurs, potentially with lethal consequences. In some of these cases initial hemostasis occurs, however, subsequent re-bleeding occurs. This may be due to fibrinolytic activity. In addition to the problems resulting from blood loss, extravasated blood components in the tissues may contribute to additional adverse outcomes including infection and the fibrotic responses seen with post-surgical tissue adhesions. Second, in some cases, hemostatic materials cause problems by entering the blood stream and causing clotting (thrombosis) within blood vessels, potentially, with lethal outcomes. Third, in some cases, wound treatment materials (including hemostatic materials) can serve as a site for subsequent infection or can result in abnormal tissue responses such as adhesion formation and/or tissue scarring, resulting in adverse medical outcomes. Improved approaches to hemostasis are needed.